In comparison with adult onset schizophrenia patients, childhood onset patients have a greater number of pre-psychotic developmental disorders. One fifth of our COS cases have earlier forms of autism spectrum disorder, and one third have motor, speech, language, attention or impulse related developmental disorders (Rapoport et al. 2009; Driver et al. 2013). In contrast, the non-psychotic siblings do not have an elevated rate of early neurodevelopmental disorders. Cognitive studies have begun within this protocol to obtain prospective measures of working memory. COS probands have significantly decreased hippocampal volume (Mattai et al 2011). Studies of anatomic hippocampal development in the healthy siblings showed no deviance from that seen for the healthy controls however a study in collaboration with colleagues at the University of Chicago show anterior hippocampal shape deviation in COS, similar to that seen for adult onset subjects, which are also shared, more subtly, by healthy COS siblings (Johnson et al. 2013). We have initiated a higher field strength (7T) study of the hippocampus in COS, their non-psychotic siblings and healthy controls. We expect to find most prominent reductions in CZ2/3 and CA4/dentate gyrus. Similarly, recent analyses also show that COS probands and their siblings show overlapping developmental deficits in the insula compared to matched controls (Moran et al. 2013a); and that sibling brain developmental defects tend to be age limited (Moran et al. 2013b). We are studying the neurocircuitry development and abnormal connectivity in COS patients and their healthy siblings. Such analyses, particularly in healthy siblings may highlight resilience factors or circuits in the brain that are relevant to early psychosis. A task related functional MRI study in collaboration with Dr. Karen Berman, NIMH, is studying functional response during two working memory tasks for probands, healthy siblings and controls. Very preliminary data suggest that probands and to a lesser extent healthy siblings demonstrate increased recruitment in several brain regions including the right DLPFC and parietal circuits suggesting a subtle functional endophenotype. A recent study explored the small world networks properties using resting state fMRI data in COS patients which suggested loss of shorter connections while the longer connections were relatively preserved (Alexander-Bloch et al. 2014). A resting state fMRI study of COS, their siblings and controls in collaboration with Dr. Stephen Gotts, NIMH, found striking abnormalities in the integration of activation in cognitive/social circuitry and motor/sensory circuits (Berman et al in preparation). Interestingly, these abnormalities bear some similarity to those seen in autism (Gotts et al in preparation). Several genetic studies are ongoing. There is a higher rate of rare copy number variants (CNVs), with 126 probands, involving 75 proband/sib pairs, and access to the current Database of Genomic Variation of over 26,000 individuals. A total of 13% of COS probands carry a rare, disease related CNV including 5 cases with the 22q11 deletion. This represents a significantly higher incidence compared to that seen for healthy controls and to that for adult onset schizophrenia patients (p<.05) (Ahn et al. 2013). To better understand the heritability of COS, exomic sequencing of 73 trios is being completed in collaboration with Matthew State, MD, (UCSF). We are also finding an 11% rate of the same rare CNVs for a group of our patients with severe early onset non-schizophrenic disorders indicating the non-specificity of CNV risk. Extramural funding has just been approved for Dr. State and his group to carry out whole genome sequencing for our COS sample. An ongoing collaborative study with Dr. Ricardo Dolmetsch, Novartis Institute, is studying neuronal activation and neurite development from induced pluripotent stem cell (iPSC) derived neurons from our childhood onset schizophrenia patients. Patients with and without rare disease associated copy number variants (CNVs) are included. Contrast groups will include unrelated healthy controls, and healthy and affected family members (some healthy carriers of risk CNVs). Evidence from iPSC-derived neurons 22q11 subjects indicated reduced L-type voltage gated calcium responses in pyramidal neurons (Psca et al. in preparation). A new study will compare changes in expression for ipsc derived neurons from our best responders and a matched group of poor clozapine responders. Finally, we continue to explore novel treatment strategies for this severely psychotic and treatment refractory population. Two inpatient treatment trials are currently ongoing; both with two week, double blind, placebo-controlled, parallel designs. The first trial explores the efficacy of trans-cranial direct current stimulation (TDCS) to (a) improve cognitive deficits by application of anodal current to bilateral DLPFC and (b) improve hallucinations by applying cathodal current to temporal cortex bilaterally (David et al. 2013). The second trial, which was just approved by the IRB, explores the efficacy of twice-daily intranasal oxytocin for enhancement of emotional cognition in COS and its effects on amygdalar-frontal emotional circuitry. We continue to advise on use of clozapine for COS and to establish guidelines for monitoring its use (Maher et al. 2013; Merikangas et al. 2013). These studies are of importance given the dearth of new treatments in child psychiatry (Merikangas et al. 2013; Rapoport. et al 2013).